Studies will be conducted with highly active antitumor compounds isolated from natural sources. Microorganisms will be used to accomplish selective chemical changes in the structures of such natural antitumor agents under the mild reaction conditions obtainable in fermentations. Where appropriate, derivatives of microbial metabolites will also be prepared and tested in suitable tumor test systems. Microbial transformations of natural antitumor drugs will continue to be developed as a general method for: a) preparing quantities of potentially active metabolites; b) providing difficult-to-synthesize drug metabolites, the availability of which will facilitate drug metabolism studies in animals and man; c) elucidating potentially important pathways of metabolism of structurally complicated antitumor compouns which may relate to mechanisms of bioactivation, bioinactivation of toxicity; and d) establishing a working basis for further structure-activity-relationship studies on such complex and biologically active compounds from nature. Specific experiments will be continued and pursued with thalicarpine, d-tetrandrine, hernandaline derivatives, Vinca alkaloids, withaferin-A, camptothecin harringtonine alkaloids, and other compounds. Structures of microbial metabolites will be determined by chemical and spectral methods, and they will be examined for antitumor activity. Mammalian metabolism studies will be initiated using available microbial metabolites as analytical standards for possible mammalian metabolites.